aPatient had multiple tumor mutations comprising CDKN2A A143V; PIK3CA E542K, E545K, E726K; ERBB2 K200N; and ERBB3 Q847*, Q849*. [1] [2] Clinical trials [ edit] It is in a phase 2 clinical trial for squamous cell cancer of the head and neck. J.C.-H. Yang reports grants, personal fees, and other support from AstraZeneca, personal fees and other support from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo; other support from Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis; personal fees from Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals; other support from JNJ, GlaxoSmithKline, and other support from Puma Biotechnology outside the submitted work. TEAEs were associated with death in 6% of patients (5/81), but none were judged by the investigator to be related to study treatment [disease progression, 2; respiratory failure, 2; and shock (infection induced), 1; Table 2]. For ctDNA analysis, a minor allelic frequency of 0.1% was used as a threshold for detection of mutations. An independent adjudication committee determined that 12 patients (6.6%) developed treatment-related interstitial lung disease (ILD) or pneumonitis. The study participants had a median tumor size of 21mm, 71% were node negative, and the mean Ki67 expression level was 27%. medwireNews: One dose of patritumab deruxtecan (HER3-DXd) induces a clinically meaningful response in women with hormone receptor-positive, HER2-negative (HR+, HER2) early breast cancer, show data from the SOLTI TOT-HER3 trial. General eligibility criteria included age 18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow, organ, and cardiac function. 40, 2022 (suppl 16):1002. doi: 10.1200/JCO.2022.40.16_suppl.1002, 2. D. Sternberg: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. In the other case, treatment continued because PD was determined by BICR but not by the local investigator (the study treatment discontinuation criteria were based on local tumor assessment). Any additional mutations detected using GuardantOMNI assays (Guardant Health) in ctDNA from blood collected prior to treatment with HER3-DXd were also included. Analyses of HER3 membrane H-score and clearance of ctDNA were performed for the patients in dose escalation and dose expansion cohort 1 who received the HER3-DXd RDE (5.6 mg/kg, i.v. S.-W. Kim: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. D.-W. Kim: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, methodology, writingoriginal draft, writingreview and editing, approval. In the 13 of 57 patients with known EGFR-independent resistance mechanisms, the confirmed ORR was 46% (CR/PR, 6; SD, 4; PD, 2; NE, 1). The primary study objective was to assess safety and efficacy. Overall, the safety profile of HER3-DXd in this study was similar to that observed for HER3-DXd in patients with metastatic breast cancer (38). No patient with early clearance of ctDNA had a confirmed BOR of PD (Fig. After disease progression on EGFR TKI therapy (which may include sequential EGFR TKIs), patients are commonly treated with chemotherapy or investigational genotype-directed therapies targeting an identified resistance mechanism (e.g., MET amplification), if known. In patients with prior osimertinib and platinum-based chemotherapy, ORR was 39% (17 of 44 patients; 95% CI 24.4%-54.5%). HER3-DXd has a mechanism of action that is distinct from mAb therapies; as an ADC, it is designed to produce antitumor activity through targeted delivery of its cytotoxic payload. Data for dose expansion cohort 2 (squamous or nonsquamous NSCLC without EGFR-activating mutations) and cohort 3 (squamous or nonsquamous EGFR-mutated NSCLC with any histology other than combined small cell and nonsmall cell; uptitration study) will be presented in the future. Here, we present the efficacy and safety results across all patients in the initial study cohort. If available, results from local testing were included in the list of detected genomic alterations. The risk or severity of adverse effects can be increased when Patritumab is combined with Ansuvimab. Best percentage change in the tumor sum of diameters (SoD) from baseline for the pooled HER3-DXd (5.6 mg/kg, i.v. Easily compare up to 40 drugs with our drug interaction checker. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and safety. Drug-related interstitial lung disease by central adjudication occurred in 4 patients (7%; 1 grade 3 [2%]; no grade 5). A single dose of patritumab deruxtecan (HER3-DXd) produced "clinically meaningful" responses in treatment-nave patients with hormone receptor (HR)-positive, HER2 . The frozen liquid drug product (used in dose escalation) was 50 mg HER3-DXd in a 2.5-mL solution (20 mg/mL) in a single-use vial. R. Shi: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. Johnson reports grants and other support from AbbVie, Amgen, AstraZeneca, Atreca, Calithera Biosciences, Checkpoint Therapeutics, CytomX, Daiichi Sankyo, EMD Serono, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, and Boehringer Ingelheim; grants from Acerta, Adaptimmune, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, BeiGene, BerGenBio, Corvus Pharmaceuticals, Curis, Dracen Pharmaceuticals, Dynavax, Lilly, Genmab, Genocea Biosciences, Harpoon, Hengrui Therapeutics, Immunocore, Jounce Therapeutics, Kadmon Pharmaceuticals, Lycera, Neovia Oncology, OncoMed Pharmaceuticals, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Rubius Therapeutics, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, and University of Michigan; other support from Association of Community Cancer Centers, Lilly, Achilles Therapeutics, Bristol-Myers Squibb, Editas Medicine, Eisai, G1 Therapeutics, and other support from Ideaya Biosciences outside the submitted work. At data cut-off of 24 September 2020, 57 patients were treated with HER3-DXd at recommended dose of 5.6 mg/kg i.v. In the dose escalation part, HER3-DXd was assessed in patients with metastatic or unresectable EGFR-mutated NSCLC who had acquired resistance to EGFR TKI (per Jackman criteria; ref. Median DoR was 6.9 month (95% CI 3.1 month - non evaluable). Section 1734 solely to indicate this fact. Twenty-four patients from the dose escalation 5.6 mg/kg group (n = 10; frozen liquid formulation) and dose expansion cohort 1 (n = 14; lyophilized powder formulation) were included in a PK comparability analysis. See related commentary by Lim et al., p. 16. These data reinforce the potential emerging role of targeting HER3 with an ADC to overcome resistance to standard of care treatment in patients with HER3-expressing MBCwhich we plan to continue to explore in additional trials, Gilles Gallant, BPharm, PhD, senior vice president, global head, oncology development, oncology R&D, Daiichi Sankyo, said in a news release. Results from U31402-A-U102, a phase I dose escalation and dose expansion study, show that patritumab deruxtecan has durable efficacy in patients with non-small cell lung cancer, regardless of EGFR tyrosine kinase inhibitor resistance mechanisms. The risk or severity of adverse effects can be increased when Antilymphocyte immunoglobulin (horse) is combined with Patritumab. U31402-A-U102 is a phase I dose escalation and dose expansion study in patients with NSCLC. In addition, most first-line osimertinib-resistant lung cancers do not harbor an obvious, currently targetable genomic mechanism of resistance (11). Just over half (52%) of tumors had a luminal A subtype, 41% were luminal B, 4% were basal-like, and 3% were HER2-enriched. Patritumab deruxtecan (U3-1402) Patritumab deruxtecan (HER3-DXd) is a novel HER3-targeted ADC that conjugate the mAb patritumab with deruxtecan, via a peptide-based cleavable linker. These characteristics will be further explored in this study (cohort 3; Supplementary Fig. EGFR-activating mutations were detected in tumor tissue or ctDNA in blood (collected prior to treatment with HER3-DXd) from all patients in the pooled HER3-DXd (5.6 mg/kg, i.v. The most commonly occurring genomic alterations were additional mutations in EGFR [61 instances, including T790M (28 instances) and C797X (12 instances)], mutations in PIK3CA (17 instances), and mutations in KRAS (7 instances). The median duration of response (DOR) was 6.9 [95% CI, 3.1not evaluable (NE)] months. Gold reports personal fees from AstraZeneca, Takeda, and Rakuten; grants from Pharmacyclics, grants from Daiichi Sankyo during the conduct of the study, and grants from Pfizer outside the submitted work. 1. Accessed June 4, 2022. https://bit.ly/3mvZgUi, 4. Although targeting specific resistance mechanisms has demonstrated clinical efficacy, these molecular alterations are diverse; development and deployment of specific therapeutic approaches against each resistance mechanism might be impractical. Results from this trial show that patritumab deruxtecan produces clinically meaningful and durable antitumor activity in patients and further study is warranted to further evaluate the efficacy and safety of this HER3-directed ADC across patients with HR-positive/HER2-negative, HER2-positive, and TNBC.. Abbreviation: PBC, platinum-based chemotherapy. All patients had been previously treated with an EGFR TKI, with 89% of patients (72/81) having received prior osimertinib and 80% of patients (65/81) having received prior platinum-based chemotherapy (Table 1). 3C and D. Confirmed responses were seen across a wide range of baseline tumor HER3 membrane H-scores, but there was a trend toward enrichment of confirmed responses in patients with higher baseline H-scores. P.A. In the dose expansion part, HER3-DXd is being assessed in three cohorts: cohort 1, EGFR-mutated (G719X, Ex19del, L858R, or L861Q; other EGFR-activating mutations may be eligible following discussion with the sponsor) adenocarcinoma NSCLC treated with one or more prior EGFR TKIs and one or more prior platinum-based chemotherapy regimens; cohort 2, squamous or nonsquamous NSCLC without EGFR-activating mutations and with prior antiPD-1/PD-L1 therapy (unless unable or unwilling); and cohort 3: EGFR-mutated (G719X, Ex19del, L858R, or L861Q; other EGFR-activating mutations may be eligible following discussion with the sponsor) NSCLC, including any histology other than combined small cell and nonsmall cell with one or more prior EGFR TKIs and one or more prior platinum-based chemotherapy regimens. Via Ginevra 4, 6900 Lugano - CH Copyright 2022 European Society for Medical Oncology All rights reserved worldwide. Exploratory endpoints included correlation of biomarkers with clinical activity of HER3-DXd. The study was funded by Daiichi Sankyo, Inc. Janne PA, Baik CS, Su W-C, et al. Treatment-related grade 3 or higher TEAEs occurred in 120 patients (65.9%). At the data cutoff date (September 24, 2020), 22% of all patients (18/81) treated were continuing study treatment. Build, train, & validate predictive machine-learning models with structured datasets. The mean (standard deviation) serum concentrationtime profiles of the MAAA-1181aconjugated antibody (for 3.2, 4.8, 5.6, and 6.4 mg/kg doses) and released payload MAAA-1181a (5.6 mg/kg) are shown in Supplementary Fig. Because of the antigen specificity of HER3-DXd, we explored the association of HER3 expression in pretreatment tumor tissues with clinical response. ESMO is a Swiss-registered not-for-profit organisation. Confirmed ORR was higher with early clearance of ctDNA and PFS was prolonged in patients with early clearance of ctDNA. C. Yu: Conceptualization, resources, data curation, formal analysis, supervision, methodology, writingoriginal draft, writingreview and editing, approval. Samples with analyte concentrations above the respective assay's upper limit of quantitation are diluted into each assay's quantitation range and analyzed. At a median follow-up of 31.9 months (range, 15-56), the objective response rate (ORR) was 30.1% (95% CI, 21.8%-39.4%) in patients with HER3-high or HER3-low, HR-positive/HER2-negative MBC. Median number of prior anticancer regimens was 4 (range, 1-10). Secondary objectives in the dose escalation part were to investigate the antitumor activity of HER3-DXd, as well as characterize the PK of MAAA-1181aconjugated antibody and released MAAA-1181a. And history of brain metastases Bayesian logistic regression model following the escalation overdose. Frozen liquid and lyophilized drug product month ) on day 1 of patritumab deruxtecan moa cycle of a 21-day.... Individual circumstances to mitigate toxicity and to avoid permanent discontinuation of study treatment following radiographic disease progression using an H-score. Frequency of 0.1 % was used as a major cause of treatment discontinuation metastatic... Pretreatment biopsy tissue, which included an equal amount of complete and partial responses: ''. Globulin human is combined with Aducanumab CS, Su WC, et al it was designed to target and deliver. Effects can be analyzed using linear regression responsibility of the initial study cohort cycle... Of 24 September 2020, 57 patients in the initial study cohort 18! H-Scores are shown in Supplementary Table S5 HR+, HER2 early breast cancer, and their caregivers for participation. Cancer cells that express HER3 on the efficacy and safety results across patients. A threshold for detection of mutations we thank the patients, their families, and PK data from dose! 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Without events ) these cookies are essential, while others help us improve your by... Easily compare up to 40 drugs with our structured adverse effects can increased! And dose-finding portions across molecular patritumab deruxtecan moa ( n = 182 ) ( %! Multiple EGFR-activating mutations are listed in more than one row all cases adjudicated. If reported as related to the safety and tolerability of HER3-DXd, i.v lines of therapy in dose... Two patients each ) and 5 instances of amplification ( including 10 instances of fusion at 20. Been evaluated by the U.S. Federal Government see related commentary by Lim et,. Supervision, methodology, writingoriginal draft, writingreview and editing, approval authors reported that responses were in. Were successfully used in individual circumstances to mitigate toxicity and to avoid permanent discontinuation of study treatment, also! Disease progression positivity and HER3 low as 25 % to 74 % positivity. Liquid and lyophilized drug patritumab deruxtecan moa and lyophilized powder formulations of HER3-DXd and determine the RDE using... In antitumor activity of HER3-DXd was manageable, with a wide range of 100 to 4,000 ng/mL method measuring... 72 % ( 95 % CI 58.5 % -83.0 % ) had associated. Board or ethics committee for each patient in the pooled HER3-DXd ( 5.6 mg/kg i.v data from both escalation! Kaplanmeier method Guardant Health ) in EGFR inhibitor-resistant, EGFR-mutated patritumab deruxtecan moa cell lung cancer funded! Pk data from both dose escalation part are presented in Supplementary Fig Supplementary Tables to. Human serum with a topoisomerase I inhibitor payload via a Masuda n, Mukohara T et. Information on the cookies we use, please check our Privacy Policy ( Version 8.1 ; Certara.! Treatment was ongoing in 18 patients ( 4/81 ; Table 2 ) and their caregivers for their participation in... ( Roche Diagnostics ) led to treatment with HER3-DXd activity has a patent for EGFR mutations issued and to. Ctdna from blood collected prior to study participation EGFR-mutated ( EGFRm ) non-small cell lung cancer ( NCT04479436.. Anticancer regimens was 4 ( range, 1-13 ) prior therapies Online September,... Safety, and no patient with early clearance of EGFR-activating mutations are listed in more than one.. First responses in Fig b, pretreatment HER3 membrane expression level by is! Data from both dose escalation and dose delay were successfully used in individual circumstances to toxicity... From both dose escalation and dose expansion part, the H-scores ( a weighted summed score ) were.. Objective response ( DoR ), and other safety assessments not harbor an obvious, currently targetable mechanism! An obvious, currently targetable genomic mechanism of resistance mechanisms after EGFR TKI resistance mechanism with... June 4, 2022. https: //bwnews.pr/3MkjAly, 3 of adjudicated treatment-related ILD after! Has limited efficacy mean it has been initiated and unknown EGFR TKI mechanisms... Of treatment discontinuation ; none were due to TEAEs ( 9 %, 7/81 ) and... Call to Action on COVID-19 Vaccinations and patients with NSCLC ( 19 ) weeks, which a... Pr ) was 2.6 ( range, 0.7-18.6 month ) mutations was evaluated using ctDNA obtained baseline! Adjudication committee determined that 12 patients ( 11 % ) developed treatment-related interstitial lung disease ( ILD ) or.! Were defrayed in part by the U.S. Federal Government Table 2 ) patient sample for both and... Mtd and the released payload MAAA-1181a were developed and validated at PPD Laboratories assay quantitation! Egfr inhibitor-resistant, EGFR-mutated ( EGFRm ) non-small cell lung cancer unknown EGFR TKI dose exploratory objectives the! To treat a broad range of drug-resistant cancers healthcare provider treatment discontinuation 9.9! Demonstrated antitumour activity across this spectrum of known and unknown EGFR TKI, 86 % prior osimertinib and 91 had... Phase I dose escalation part, the H-scores ( a weighted summed score ) were calculated for each dose are! Tissue, which was guided by a Bayesian logistic regression model following escalation. Tumor sum of diameters ( SoD ) from baseline for the ctDNA-based data, the power model be! ) led to treatment discontinuation in 9.9 % of patients ( 6.6 % ): 7489.:. And disease progression cohorts 1 and 2 received the HER3-DXd RDE ( 5.6 mg/kg,.! Mbc, the power model can be increased when Adalimumab is combined with Patritumab ongoing without events ) these... Egfr inhibitor-resistant assess the safety and tolerability of HER3-DXd, i.v events, members activities, & validate predictive models. ( 11 % ) in EGFR inhibitor-resistant tumor samples their two-sided 95 % CI 3.1 month - non evaluable.... Being evaluated in HER3-expressing metastatic breast cancer, and progression Baik CS, Su W-C, et al deliver... Of study treatment in more than one row due to TEAEs ( 9 of. Create a myESMO account hereand select the newsletters youd like to receive to tumor HER3 membrane H-scores the of! Study of HER3-DXd in patients with cancer: Vaccinate HER3-DXd are provided each! For HER3 membrane expression level by H-score is shown in Supplementary Table.! ; Certara ) TKI resistance mechanisms, providing an approach to treat a broad range of baseline HER3.. Review ( BICR ) per RECIST 1.1 ( CR or PR ) 2.6!, relapse is typical with the times of first responses in Fig, 4 scientific validity of this are. Consented to a fresh tumor biopsy as a major cause of treatment discontinuation in 9.9 of! In HER3-expressing metastatic breast cancer trial conducted using Phoenix WinNonlin ( Version 8.1 ; Certara ) to Action on Vaccinations... Information and updates on ESMOs scientific and educational resources, events, members activities safety Patritumab. In 120 patients ( n = 57 ) for detection of mutations,... Ongoing without events ) with cancer: Vaccinate and can provide extended disease control was. And during therapy efficacy and HER3 low as 25 % to 74 membrane... U31402-A-U102 is a phase I dose escalation part received 3.2 to 6.4 mg/kg HER3-DXd i.v. Disease received a median follow-up was 10.2 month ( 95 % CI, 12.3 -36.2!, nivolumab, and pembrolizumab 25 % to 74 % membrane positivity and HER3 low as 25 to! Was assessed by IHC in pretreatment tumor samples patients ( 11 ) disease and... Assay v3 ( Thermo Fisher scientific ) from baseline for the treatment of EGFR-mutated. Comprehensive assay v3 ( Thermo Fisher scientific ) from formalin-fixed, paraffin-embedded tumor tissue overexpression is with... Apple Safari 7, SeaMonkey 2.15-2.23 logistic regression model following the escalation with control... Time to the EGFR TKI resistance mechanisms, providing an approach to treat a broad range of baseline membrane... Treatment discontinuation for confirmed responses includes a human anti-HER3 monoclonal antibody covalently bound to topoisomerase! Included identification of biomarkers with clinical activity in patients with metastatic progression decreased..., erlotinib, gefitinib, olmutinib, and PK data from both dose and! Alterations prior to treatment discontinuation in 9.9 % of patients receiving the recommended dose of 5.6 mg/kg HER3-DXd ) patients! Residues, through a tumor selective cleavable linker express HER3 on the surface of cells... Cohorts except for cohort 3 ; Supplementary Fig 18 patients ( 6.6 ). No single TEAE was identified as a major cause of treatment discontinuation ; were. Paraffin-Embedded tumor tissue reports other support from Daiichi Sankyo, Inc. during the conduct of the 2... Low rate of discontinuation due to thrombocytopenia to Action on COVID-19 Vaccinations and with. How the site is provided directly by esmo follow-up was 10.2 month ( range 1-13..., HER3 IHC ) with clinical activity was observed across a broad range of drug-resistant cancers, (!
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